Closed-Angle Glaucoma: A Study of the Mechanism of Angle Closure

Presented in this thesis is a new conception of the mechanism underlying the development of closed angle glaucoma. It is based upon a study of the ocular tension and facility of aqueous outflow in normal eyes and those affected by the disease, in response to provocative tests, together with observations upon cases of chronic closed angle glaucoma and upon the apparently healthy eyes of cases wherein the disease is unilateral. The development of currently accepted views on the aetiology of closed angle glaucoma is traced in a review of the literature on the subject and it is shown that the disease is believed to be due to mechanical obstruction of the angle of the anterior chamber by the root of the iris in an eye wherein the lens is disproportionately large. It has been generally held until now that in an eye affected by this disease the ocular tension and facility of aqueous outflow between attacks of hypertension are completely normal and that the angle of the anterior chamber at these times is open and functioning freely. That this view is erroneous in in many cases, however, is the deduction to be drawn from the work presented in this thesis, for all the evidence supports the view that even in the early stages of the disease a variable portion of the angle of the anterior chamber is habitually closed and that the ocular tension and facility of aqueous outflow in such an eye, although still within the accepted limits of normality, is in fact already abnormal for the eye in question. The darkroom test is studied in detail and an analysis of the results of the test on normal eyes and those affected by closed angle glaucoma is presented. It is shown, contrary to the generally accepted view, that the rise in ocular tension occasioned by the test is influenced by the initial tension in the eye tested and probably by the degree of angle closure existing prior to the test. It is calculated that a rise in ocular tension of over 8.5 mm. Hg with the darkroom test is evidence in favour of a diagnosis of closed angle glaucoma. The development of the tonographic method of measuring the facility of aqueous outflow is outlined and and a new provocative test, the "darkroom outflow test" is described. In this test, measurements of the facility of aqueous outflow are made before and after one hour in the dark; the occurrence of angle closure being indicated by a measurable fall in the level of aqueous outflow. From a study of the results of this test on normal eyes and those affected by closed angle glaucoma it is concluded that a fall in the outflow level of at least 30% with this test is of significance. Contrary to the generally accepted view, it is shown that in cases of closed angle glaucoma, even where the resting ocular tension is within normal limits, the facility of outflow is lower than that found in comparable normal eyes, indicating the existence of some degree of angle closure in the affected eyes. It is also demonstrated that the rise in ocular tension occuring with the darkroom test is directly related to the level of aqueous outflow existing prior to the test and thus to the degree of angle closure present at that time. From a study of the effect of the darkroom test and the darkroom outflow test on normal eyes it is concluded, contrary to the generally accepted view, that variations in the rate of aqueous inflow play a more important part in the causation of changes in ocular tension than do alterations in the rate of aqueous outflow. (Abstract shortened by ProQuest.)

Constructing Policy Success for UK Energy Feedback

Energy feedback tools are commonly used to promote energy saving. In the UK, energy feedback provision (currently via an In-Home Display) is part of the government-mandated roll-out of smart meters to all homes by 2020. A core assumption underlying this widespread provision is that information, or evidence, can lead to positive changes in action. This is analogous to assumptions underlying the notion of ‘Evidence-Based Policy’, which raises questions about how users, researchers and policymakers go about using evidence in aiming for a ‘successful’ outcome. In addition the ‘policy feedback’ research agenda has asked how policies alter the landscapes within which they operate by, for example, affecting relationships between actors. Via an in-depth review of DECC (now BEIS) policy literature over 2010-2016, the UK smart meter roll-out was analysed in terms of how its energy feedback focussed measures may be deemed as ‘successful’. Findings include that direct energy savings played a smaller role than might be expected, and translation from one success measure to another was repeatedly observed. A key conclusion is that acting on feedback requires an assessment of success, but such assessment is highly contextual, for consumers and policymakers alike. Ways to increase reflexivity in this area are discussed

In Situ Contaminated Sediments Project – Work Package 1A Report

Project aims Defra is seeking to understand the magnitude of risks (e.g. to aquatic ecology and human health) or impacts (e.g. on the way that water bodies are managed) posed by contaminated sediment in England, as part of its work towards meeting its environmental objectives. In the context of this project, in-situ contaminated sediment is defined as: Chemically contaminated sediment within the water column, bed, banks and floodplain of a surface water body that has been transported alongside the normal sediment load and deposited by fluvial or coastal processes. This project considers the risk posed by non-agricultural diffuse pollution sources in England that result in the contamination of in-situ sediments (for example, contamination from toxic metals, hydrocarbons and surfactants). The scope encompasses both freshwater and marine sediments in England and extends to one nautical mile off-shore (the seaward limit of coastal waters under the Water Framework Directive (WFD) in England). Previous national strategies, including the 2007 Defra UK Strategy for Managing Contaminated Marine Sediments (CDMS), focussed on characterising the risks associated with contaminated sediments in the marine environment. However, while extensive research has been carried out in many locations (including as part of WFD implementation studies) and for particular sources of contamination (e.g. historical metal mining; Environment Agency, 2008) there has not been a comprehensive overview of sediment contamination on a national scale. This project seeks to build on the existing evidence base, drawing together information on the freshwater environment to complement that already gathered for marine waters. This project’s overall aim is to provide a sound evidence base on the contamination of in-situ sediments, which can underpin the development of tools and methods that will help Defra, the Environment Agency and other bodies engaged in regulation and protection of water quality

Generalized Buneman pruning for inferring the most parsimonious multi-state phylogeny

Accurate reconstruction of phylogenies remains a key challenge in evolutionary biology. Most biologically plausible formulations of the problem are formally NP-hard, with no known efficient solution. The standard in practice are fast heuristic methods that are empirically known to work very well in general, but can yield results arbitrarily far from optimal. Practical exact methods, which yield exponential worst-case running times but generally much better times in practice, provide an important alternative. We report progress in this direction by introducing a provably optimal method for the weighted multi-state maximum parsimony phylogeny problem. The method is based on generalizing the notion of the Buneman graph, a construction key to efficient exact methods for binary sequences, so as to apply to sequences with arbitrary finite numbers of states with arbitrary state transition weights. We implement an integer linear programming (ILP) method for the multi-state problem using this generalized Buneman graph and demonstrate that the resulting method is able to solve data sets that are intractable by prior exact methods in run times comparable with popular heuristics. Our work provides the first method for provably optimal maximum parsimony phylogeny inference that is practical for multi-state data sets of more than a few characters.Comment: 15 page

Robinson-Foulds Supertrees

<p>Abstract</p> <p>Background</p> <p>Supertree methods synthesize collections of small phylogenetic trees with incomplete taxon overlap into comprehensive trees, or supertrees, that include all taxa found in the input trees. Supertree methods based on the well established Robinson-Foulds (RF) distance have the potential to build supertrees that retain much information from the input trees. Specifically, the RF supertree problem seeks a binary supertree that minimizes the sum of the RF distances from the supertree to the input trees. Thus, an RF supertree is a supertree that is consistent with the largest number of clusters (or clades) from the input trees.</p> <p>Results</p> <p>We introduce efficient, local search based, hill-climbing heuristics for the intrinsically hard RF supertree problem on rooted trees. These heuristics use novel non-trivial algorithms for the SPR and TBR local search problems which improve on the time complexity of the best known (naïve) solutions by a factor of Θ(<it>n</it>) and Θ(<it>n</it>²) respectively (where <it>n </it>is the number of taxa, or leaves, in the supertree). We use an implementation of our new algorithms to examine the performance of the RF supertree method and compare it to matrix representation with parsimony (MRP) and the triplet supertree method using four supertree data sets. Not only did our RF heuristic provide fast estimates of RF supertrees in all data sets, but the RF supertrees also retained more of the information from the input trees (based on the RF distance) than the other supertree methods.</p> <p>Conclusions</p> <p>Our heuristics for the RF supertree problem, based on our new local search algorithms, make it possible for the first time to estimate large supertrees by directly optimizing the RF distance from rooted input trees to the supertrees. This provides a new and fast method to build accurate supertrees. RF supertrees may also be useful for estimating majority-rule(-) supertrees, which are a generalization of majority-rule consensus trees.</p

MELCOR analyses of severe accident scenarios in Oconee, a B&W PWR plant

This paper presents the results and insights gained from MELCOR analyses of two severe accident scenarios, a Loss of Coolant Accident (LOCA) and a Station Blackout (TMLB) in Oconee, a Babcock & Wilcox (B&W) designed PWR with a large dry containment, and comparisons with Source Term Code Package (STCP) calculations of the same sequences. Results include predicted timing of key events, thermal-hydraulic response in the reactor coolant system and containment, and environmental releases of fission products. The paper also explores the impact of varying concrete type, vessel failure temperature, and break location on the accident progression, containment pressurization, and environmental releases of radionuclides

Membrane Hsp70 — a novel target for the isolation of circulating tumor cells after epithelial-to-mesenchymal transition

The presence of circulating tumor cells (CTCs) in the peripheral blood is a pre-requisite for progression, invasion, and metastatic spread of cancer. Consequently, the enumeration and molecular characterization of CTCs from the peripheral blood of patients with solid tumors before, during and after treatment serves as a valuable tool for categorizing disease, evaluating prognosis and for predicting and monitoring therapeutic responsiveness. Many of the techniques for isolating CTCs are based on the expression of epithelial cell surface adhesion molecule (EpCAM, CD326) on tumor cells. However, the transition of adherent epithelial cells to migratory mesenchymal cells (epithelial-to-mesenchymal transition, EMT)—an essential element of the metastatic process—is frequently associated with a loss of expression of epithelial cell markers, including EpCAM. A highly relevant proportion of mesenchymal CTCs cannot therefore be isolated using techniques that are based on the “capture” of cells expressing EpCAM. Herein, we provide evidence that a monoclonal antibody (mAb) directed against a membrane-bound form of Hsp70 (mHsp70)—cmHsp70.1—can be used for the isolation of viable CTCs from peripheral blood of tumor patients of different entities in a more quantitative manner. In contrast to EpCAM, the expression of mHsp70 remains stably upregulated on migratory, mesenchymal CTCs, metastases and cells that have been triggered to undergo EMT. Therefore, we propose that approaches for isolating CTCs based on the capture of cells that express mHsp70 using the cmHsp70.1 mAb are superior to those based on EpCAM expression

Immune reconstitution after autologous hematopoietic stem cell transplantation in Crohn's disease: current status and future directions. A review on behalf of the EBMT Autoimmune Diseases Working Party and the autologous stem cell transplantation in refractory CD—low intensity therapy evaluation study investigators

Patients with treatment refractory Crohn’s disease (CD) suffer debilitating symptoms, poor quality of life, and reduced work productivity. Surgery to resect inflamed and fibrotic intestine may mandate creation of a stoma and is often declined by patients. Such patients continue to be exposed to medical therapy that is ineffective, often expensive and still associated with a burden of adverse effects. Over the last two decades, autologous hematopoietic stem cell transplantation (auto-HSCT) has emerged as a promising treatment option for patients with severe autoimmune diseases (ADs). Mechanistic studies have provided proof of concept that auto-HSCT can restore immunological tolerance in chronic autoimmunity via the eradication of pathological immune responses and a profound reconfiguration of the immune system. Herein, we review current experience of auto-HSCT for the treatment of CD as well as approaches that have been used to monitor immune reconstitution following auto-HSCT in patients with ADs, including CD. We also detail immune reconstitution studies that have been integrated into the randomized controlled Autologous Stem cell Transplantation In refractory CD—Low Intensity Therapy Evaluation trial, which is designed to test the hypothesis that auto-HSCT using reduced intensity mobilization and conditioning regimens will be a safe and effective means of inducing sustained control in refractory CD compared to standard of care. Immunological profiling will generate insight into the pathogenesis of the disease, restoration of responsiveness to anti-TNF therapy in patients with recurrence of endoscopic disease and immunological events that precede the onset of disease in patients that relapse after auto-HSCT

Immune-phenotyping and transcriptomic profiling of peripheral blood mononuclear cells from patients with breast cancer: identification of a 3 gene signature which predicts relapse of triple negative breast cancer

Background: Interactions between the immune system and tumors are highly reciprocal in nature, leading to speculation that tumor recurrence or therapeutic resistance could be influenced or predicted by immune events that manifest locally, but can be detected systemically. Methods: Multi-parameter flow cytometry was used to examine the percentage and phenotype of natural killer (NK) cells, myeloid-derived suppressor cells (MDSCs), monocyte subsets and regulatory T (Treg) cells in the peripheral blood of of 85 patients with breast cancer (50 of whom were assessed before and after one cycle of anthracycline-based chemotherapy), and 23 controls. Transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) in 23 patients were generated using a NanoString gene profiling platform. Results: An increased percentage of immunosuppressive cells such as granulocytic MDSCs, intermediate CD14++CD16+ monocytes and CD127negCD25highFoxP3+ Treg cells was observed in patients with breast cancer, especially patients with stage 3 and 4 disease, regardless of ER status. Following neoadjuvant chemotherapy, B cell numbers decreased significantly, whereas monocyte numbers increased. Although chemotherapy had no effect on the percentage of Treg, MDSC and NK cells, the expression of inhibitory receptors CD85j, LIAR and NKG2A and activating receptors NKp30 and NKp44 on NK cells increased, concomitant with a decreased expression of NKp46 and DNAM-1 activating receptors. Transcriptomic profiling revealed a distinct group of 3 patients in the triple negative breast cancer (TNBC) cohort who expressed high levels of mRNA encoding genes predominantly involved in inflammation. The analysis of a large transcriptomic dataset derived from the tumors of patients with TNBC revealed that the expression of CD163, CXCR4, THBS1 predicted relapse-free survival. Conclusions: The peripheral blood immunome of patients with breast cancer is influenced by the presence and stage of cancer, but not by molecular subtypes. Furthermore, immune profiling coupled with transcriptomic analyses of peripheral blood cells may identify patients with TNBC that are at risk of relapse after chemotherapy